Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases

Abstract

Hypoxia-inducible factor (HIF) deregulation contributes to the Warburg effect. HIF consists of an unstable α subunit and a stable β subunit. In the presence of oxygen, HIFα becomes prolyl hydroxylated by members of the EglN (also called PHD) family, leading to its proteasomal degradation. Under hypoxic conditions, EglN activity is diminished and HIF levels rise. EglN1 is the primary HIF prolyl hydroxylase with EglN2 and EglN3 playing compensatory roles under certain conditions. EglN2 and EglN3 also appear to play HIF-independent roles in regulating cell proliferation and apoptosis, respectively. The EglNs belong to a large family of 2-oxoglutarate-dependent dioxygenases that includes the TET DNA hydroxymethylases and JmjC-containing histone demethylases. Members of this superfamily can be inhibited by endogenous metabolites, including fumarate and succinate, which accumulate in tumors that have fumarate hydratase (FH) or succinate dehydrogenase (SDH) mutations, respectively, as well as by the 2-hydroxyglutarate detected in isocitrate dehydrogenase (IDH) mutant tumors. 2-Oxoglutarate-dependent dioxygenases therefore provide a link between altered metabolism and cancer.

Fig 1. 2-Oxoglutarate-dependent Dioxygenase Reaction

2-Oxoglutarate-dependent enzymes require 2-oxoglutarate (also called alpha ketoglutarate), oxygen, and reduced iron to hydroxylate their substrates. 2-oxoglutarate is decarboxylated to succinate during the reaction. In the cases of histone demethylases a methyl group is hydroxylated and the resulting hydroxymethyl group is spontaneously given off as formaldehyde. These enzymes are variably susceptible to inhibition by Krebs Cycle intermediates such a succinate and fumarate, to 2-hydroxyglutarate, and to reactive oxygen species.

Fig 2. Central Role of HIF in Warburg Metabolism

Many oncogenic mutations lead to increased HIF accumulation, which promotes the Warburg Effect. Increase Myc expression and loss of p53 function can also contribute to such metabolic changes.